Cholesterol is an extremely important molecule in the body. It is a key component of cell membranes and is utilized in the formation of steroid hormones and bile acids. Because of its insolubility, it does not travel freely in the bloodstream but is carried by particles called lipoproteins. There are several different types of lipoprotein and the fate of cholesterol is different depending on which type of lipoprotein carries it. Low density lipoproteins (LDL) can deposit excess cholesterol on the arterial linings while high density lipoprotein (HDL) can remove excess cholesterol from peripheral tissues and transport it to the liver for excretion. LDL, the major carrier of plasma cholesterol, is taken up by the liver and peripheral cells, largely via receptors that recognize apoprotein B. The cytoplasmic pool of cholesterol is derived partly from LDL and partly by endogenous biosynthesis (Chapman, M J et al. Curr Med Res Opin., 2005, 21(Suppl 6):S17-22).
Regulation of plasma cholesterol levels has to be tightly controlled in order to insure adequate supplies for the cells but not so much as to result in cholesterol deposition and atherosclerosis. Excretion of bile salts is the major route for regulating cholesterol levels. In the liver, excess cholesterol is converted to bile acids which, after secretion in the bile, are ultimately excreted in the feces. There is an additional pathway for lowering plasma cholesterol levels and that is called reverse cholesterol transport. This process is mediated by HDL which is able to absorb cholesterol from peripheral tissues and from arterial wall macrophages and carry it to the liver for conversion to bile acids and excretion.
Lowering cholesterol is important for everyone, including younger, middle-aged, and older adults, and people with or without heart disease and/or stroke. Lowering high cholesterol levels lessens the risk for developing heart disease and reduces the chance of a heart attack or dying of heart disease (Stone, N J, Endocrinol Metab Clin North Am., 1990, 19(2):321-44); Chapman, M J Curr Med Res Opin., 2005, 21(Suppl 6):S17-22).
In accordance with the National Heart, Lung, and Blood Institute's Cholesterol Education Program (NCEP), everyone age 20 and older should have their cholesterol and triglyceride levels measured at least once every five years. HDL cholesterol protects against heart disease. This means that higher numbers of HDL cholesterol are better. A level less than 40 mg/dL is considered low and a major risk factor for the development of coronary artery disease. HDL levels of 60 mg/dL or more help to lower your risk for heart disease. Triglycerides also can raise heart disease risk. Levels that are borderline high (150-199 mg/dL) or high (200 mg/dL or more) may require treatment for some people. The NHLBI classification of the optimal level of LDL cholesterol is less than 100 mg/dL. Borderline high LDL cholesterol is 130-159 mg/dL, and very high is 190 mg/dL and above. High LDL cholesterol always requires attention. One's chance of developing coronary artery disease increases with the presence of one or more heart disease risk factors, such as high blood pressure, diabetes, and/or an early family history of heart disease. It is estimated that 7 million American adults have high cholesterol. While other factors such as high blood pressure, diabetes, smoking, or a family history, contribute to high cholesterol, more than half of all heart disease is associated with lipid abnormalities. Decreasing total cholesterol by 10% can result in a 30% reduction in coronary heart disease incidence.
This is especially true for people who have already suffered a heart attack. If plaques have narrowed the arteries around the heart and restricted the flow of oxygen-rich blood to the heart's muscles it may cause coronary artery disease. There are several ways to treat high cholesterol, such as by switching to a cholesterol-lowering diet (called the TLC diet), increasing physical activity, and reducing obesity. When the LDL level is greater than 160 mg/dL, it may be necessary to take cholesterol-lowering drugs together with TLC treatment to lower LDL cholesterol levels sufficiently.
Medications that reduce blood cholesterol levels include, but are not limited to, (a) cholesterol sequestration drugs; (b) triglyceride-lowering drugs; and (c) cholesterol pathway blockers (statins). Cholesterol sequestration drugs (resins), such as cholestyramine (Questran) and colestipol (Colestid), are used to lower cholesterol indirectly by binding with bile acids in the intestinal tract. The liver makes bile acids, which are needed for digestion, from cholesterol. By sequestering bile acids, resins induce the liver to make more bile acids, thus reducing the cholesterol in the bloodstream (Schmitz, G and Langmann, T Vascul Pharmacol., 2006, 44(2):75-89; Schmitz, G et al. Clin Chem Lab Med., 2003, 41(4):581-9). Triglyceride-lowering drugs include fibrates, such as gemfibrozil (Lopid) and fenofibrate (Tricor), and the vitamin niacin (nicotinic acid), which reduce triglyceride production and remove triglycerides from circulation. They can also increase HDL (Gotto, A M Jr. Am Heart J., 2002, 144(6):S33-42; Miller, J P et al. Clin Chim Acta., 1988, 178(3):251-9). Statins are competitive inhibitors of HMG-CoA reductase, the key enzyme in the cholesterol biosynthesis pathway. This depletes cholesterol in liver cells, which causes the liver cells to remove cholesterol from the blood (Rodenburg, J et al. Pediatr Endocrinol Rev., 2004, 2(Suppl 1):171-80; Gylling, H et al. Curr Opin Investig Drugs., 2006 March, 7(3):214-8). Statins can reduce LDL cholesterol by up to 40 percent. Statins may also help the body reabsorb cholesterol from plaques that accumulate on the walls of the arteries, thus making them less likely to cause complications such as a heart attack or stroke. Statins include fluvastatin (Lescol), lovastatin (Mevacor), simvastatin (Zocor), pravastatin (Pravachol) and atorvastatin (Lipitor) (Stroes, E et al. Curr Med Res Opin., 2005, 21(Suppl 6):S9-16).
However, some people are unusually sensitive to the effects of some cholesterol-reducing drugs. For example, gemfibrozil may increase the risk of some types of cancer, and may cause gallstones or muscle problems. HMG-CoA reductase inhibitors (statins) may damage the liver or muscles (Dale, K M et al. JAMA, 2006 Jan. 4, 295(1):74-80). Cholesterol-reducing drugs may interact with other medicines—the effects of one or both of the drugs may change, thus interfering with the therapeutic effect, or the risk of side effects may be greater. None of these procedures can cure coronary heart disease (CHD). They open the vessels, improving blood flow and relieving symptoms, but lifestyle changes or medication will still be needed to halt the progress of the underlying disease (Jacobs, E J et al. J Natl Cancer Inst., 2006, 98(1):69-72; Rodenburg, J et al. Pediatr Endocrinol Rev., 2004, 2(Suppl 1):171-80).
Surgical procedures for cholesterol reduction include gastric stapling performed on severely obese patients, during which the stomach walls are stapled together to create a smaller stomach pouch, thus reducing the volume of the stomach by vertical banded gastroplasty, video-assisted laparoscopy, or open-surgery methods (Almhanna, K et al. Am J Hematol., 2006 February, 81(2):155-156; Health News., 2005 July, 11(7):14). Also, bariatric surgery provides a significant improvement in cases of high cholesterol; however, it carries the usual pain and risks of any major gastrointestinal surgical operation and patients have a lifelong risk of nutritional deficiencies (Korenkov, M et al. Curr Opin Gastroenterol., 2005, 21(6):679-83). Other cholesterol reducing measures include gastric bypass, which produces a feeling of stomach fullness, thereby decreasing food intake (Jones, K B Jr Int Surg., 2004, 89(1):51-7) or gastroplasty which reroutes the digestive system, but it also restricts the amount of food that can be eaten by making the stomach smaller (Loewe, C, Am J Forensic Med Pathol., 2005, 26(3):297-30). Potential side effects resulting from lap band and gastroplasty include “dumping syndrome” which is a combination of nausea, chest, and abdominal cramps, sweating, and diarrhea. Other risks and complications include malabsorption, vitamin deficiencies, and chronic abdominal pain (Daetwiler, S Obes Surg., 2005, 15(9):1341-3; Almhanna, K et al. Am J Hematol., 2006 February, 81(2):155-156; Srikanth, M S Obes Surg., 2005, 15(8):1165-70). In essence, the current cholesterol reduction procedures are far from optimal.
Although magnetic microparticles are already being successfully used in commercial DNA isolation, their unique properties offer distinct advantages, such as higher surface area, super-paramagnetism and tunable magnetic response, that can be used in biomedical applications such as organ/tissue targeted diagnosis and drug delivery, detoxification of biological fluids, magnetically controlled drug delivery, magnetic resonance imaging (MRI) contrast enhancement and magnetic cell separation (Thorek, D L et al. Ann Biomed Eng., 2006 January, 34(1):23-38; Gu, H, Chem Commun (Camb)., 2006 Mar. 7, (9):941-9). In biomedical applications, the magnetic particles either form the core (Fe3O4 or Fe2O3), which is functionalized by surface modification with biocompatible polymers and ligands, or include biocompatible polymers coacervated with magnetic nanoparticles, as shown in the data described herein. Additional magnetic particles, containing iron, cobalt, nickel, aluminum or cobalt/silica, are under investigation. In essence, the magnetic particles can be considered active substrates for selective biochemical reactions. The process of polymerization not only provides effective encapsulation of individual nanoparticles but also controls the growth in size, thus yielding a better overall size distribution. It is important to study the magnetic properties of nanopowders comprising polymer-coated particles and, in particular, to determine the role of the polymer in controlling the magnetic interactions. It is likely that the polymer coating directly affects interparticle separation and thus alters the exchange interactions that are the basis for super-paramagnetic or ferromagnetic behavior (Alexiou, C et al. Eur Biophys J., 2006 Jan. 31, 1-5).